Overdiagnosis

Making people sick in the pursuit of healthDrs Gilbert Welch, Lisa Schwartz, Steven Woloshin

Screening for prostate cancer

• « Screening for prostate cancer has become the poster child of overdiagnosis in cancer. »Welch, Schwartz and Woloshin.

• « A profit-driven public health disaster .» Prof. Ablin, discovererof PSA

Prostate cancer overdiagnosis

Prostate cancer overdiagnosis

• 2.3 million US men diagnosed in the last quarter of XXth Century.• Between 1 and 2 per thousand died in hospital following surgery.• 17% required a second surgical intervention.• 28% require to wear a diaper.• More than half have become impotent.• 33% of those treated with radiotherapy still have to put up with chronic diarrhea or

imperative bm, 2 years after treatment.

Reservoir of overdiagnosis for prostate cancer: men killed in accidents and found to have prostate cancer

20-29 ans 8,6%

30-39 31%

40-49 40%

50-59 46%

60-69 68%

70-79 83%

Conclusion

• « All screening programmes do harm. »Angela Raffle and MuirGray

• Some do good as well, at reasonable cost, in terms of humansuffering and resources.

• Prostate cancer screening does not.

References• 1. Dr.H.Gilbert Welch, Dr. Lisa M Schwartz, Dr. Steven Woloshin. Overdiagnosed. Making People Sick

in the Pursuit of Health. Beacon Press, Boston 2011.• Richard J. Ablin. « The Great Prostate Mistake » NewYork Times, March 10,2010;

http://www.nytimes.com/2010/03/10/opinion/10Ablin.html?pa.• Nortin M. Hadler. Rethinking Aging. Growing Old and Living Well in an Overtreated Society. UNC

Press, Chapel Hill, 2011.• GL Andriole,RL Grubb, SS Buys et al. for the PLCO Project Team. « Mortality Results from a

Randomized Prostate-Cancer Screening Trial ». NEJM 360 (2009): 1310-19.• FH Schroder, J Hugosson, MJ Roobol et al for the ERSPC Investigators, »Screening and Prostate-

Cancer Mortality in a Randomized European Study », NEJM 360 (2009)1320-28.• A.Raffle, Muir Gray. Screening: Evidence and Practice. Oxford University Press, NewYork, 2007.

Thank you

Fernand Turcotte, M.D., M.P.H., FRCPCUniversité Laval.

Presentation for ARCC Conference 2015

Monday, May 25, 2015

Rocco RossiPresident & CEO Prostate Cancer Canada@roccorossiTOrocco@prostatecancer.ca

Prostate Cancer Canada

Prostate Cancer Statistics

PSA Recommendations• Conflicting views regarding screening using PSA test

– No screening • US Task Force, Canadian Task Force

– Establishing baseline• European Association of Urology, Melbourne Consensus

• All looking at same evidence but coming up with different recommendations

Prostate Cancer Screening RCTs

ERSPC Follow up # needed to screen # needed to treat

9 years 1410 48

11 years 979 35

13 years 781 27

• Most credible prostate cancer screening trial (ERSPC) showed the longer you follow the cohort, the lower the number needed to screen and treat to save one life

• ERSPC screening trial shows substantial mortality reduction

Early Detection• Screening reduces the number of men dying from

prostate cancer

• The cases of advanced (metastatic) prostate cancer would double, resulting in an estimated 13-20 percent increase in annual prostate cancer deaths

• Mortality from prostate cancer has dropped by 40% over the last 20 years

5-Year Relative Survival Rate by Stage at Time of Diagnosis*

Stage 5-year Relative Survival Rate

Local >90%

Metastatic 28%

*American Cancer Society. Survival Rates for Prostate Cancer. 2015.

“Smart Screening”• Prostate Cancer Canada believes in

“smart screening”

• Men are encouraged to be tested to establish a baseline number in their 40s with follow-up based on individual’s risk profile

• PSA test not perfect but is currently the best indicator that something may be wrong with the prostate

• While there are controversies with the PSA test, high numbers serve as a red flag for further investigation

• PSA test is only one part of the diagnostic process

Active Surveillance

• Early detection saves lives but cannot distinguish between low and high risk disease

– Risk of over treatment

• One method to mitigate over treatment is to use Active Surveillance

• Not every case requires immediate treatment

Funding New ResearchDistinguishing between aggressive and indolent prostate cancers

Dr. John LewisEdmonton, AB

Dr. Robert DaySherbrooke, QC

Dr. Bharati BapatToronto, ON

Take Home Messages

• Screening reduces the number of men dying of prostate cancer; early detection saves lives

• Baseline PSA testing of men in their 40s is a good predictor for future prostate cancer risk

• PSA is part of risk profile in diagnosis of prostate cancer

Clinical Solutions to the Over-Diagnosis and Treatment of Prostate CancerAndrew LoblawProfessorDepartment of Radiation OncologyInstitute of Health Policy, Management and EvaluationUniversity of Toronto

ARCC, MontrealMay 25 2015

Objectives To review the data fueling the controversy of

PSA screening To discuss current and future management

strategies to improve outcomes and decrease cost

Faculty Disclosure StatementFinancial Disclosure (within 2 years)Grants/Research Support:

– Sanofi, Paladin

Honoraria: – Amgen, AstraZeneca, Elekta, GE, Janssen, Paladin, Sanofi

Advisory Boards: – Amgen, Astellas, Janssen, Sanofi

Financial Group:– TSRCC Radiation Oncology Associates, Sunnybrook International

Non-Financial DisclosureMember of:

– Prostate Cure Foundation, Prostate Cancer Canada, CCO Program in Evidence-Based Care, ASCO Clinical Practice Guidelines Cmt

Plagiarism Disclosure

• I have presented some of these slides at previous talks

Screening for Prostate Cancer

PC Mortality over 20 years

Canadian Cancer Society Stats 2013

PSA 31 x105

18 x105

42% reduction1800 men / yr

Treatment Effect on Mortality

Etzioni R et al., Cancer 2012

ERSPCSchroder F et al. Lancet epub Aug 7 2014182,160 men 50-74y162,388 men 55-69yCSS HR (ITT) 0.79 (95% CI: 0.69-0.91) at 13yCSS HR (eff) 0.73 (95% CI 0.61-0.88) NNS 781NNT 27No diff in OS (only 10% power)MFS HR 0.33

PLCOAndriole GA et al. JNCI 104(2), 201276,685 men 55-74yHR (ITT) 1.09 (95% CI: 0.87-1.36) at 13yNon-compliance control 52%Non-compliance screen 20%

Which Weigh More?

Conclusion: Green balls weigh more

Which Weigh More?

Conclusion: Green balls weigh the same?

Green BallsBlue Balls

PSA Screening – Real Effect?

Hugosson J et al., Lancet 2010

50-70yPSA q2y

NNS 293NNT 12CSS ARR 0.5%HR 0.56 ITTHR 0.44 efficacy

Cdn Task Force 2014

Cdn Task Force on Preventive Health Care CMAJ 2014

Most common advice?Shared decision-makingfor men 50-70y

Why the Confusion?

1. Early diagnosis too harmful– Diagnostic process has harms– Diagnosis = Treatment for all patients

2. For those needing treatment, treatments not effective enough

3. (Too expensive?)

Smart Diagnosis

Risk Adapted

www.prostaterisk.ca

Long-Term Risk of PCa Ages 44-50y

Any CancerPalpable CancerAdvanced Cancer

Lilja H et al., Cancer 2011

Need to consider harms of biopsyN=41,682

Nam et al, J Urol,183(3):963-8, 2010

Confirmed from:SEER:Loeb et al, J Urol, 186(5): 1830-4, 2011

ERSPC: Loeb et al, Eur Urol, 61(6): 1110-4, 2012

TP vs TRUS Bx

Transperineal Biopsy

Hossak T et al., J Urol 2012

vs. TRUS bx:• more ant tumors: 16 v 12%, p=0.046• R1 rate: 69 v 34% for ant tumors• smaller size: 1.4 v 2.1cm, p=0.03• lower pT3 rate: 13 vs 28%, p=0.03

Complications after TP Bx

0.076% sepsis risk>50x lower risk than TRUSbx

Chang DTS et al., Nat Rev Urol 2013

Smart Biopsies:The Value of MRI

T2-weighted image ADC map (mm2/s)

DCE

50

100

150

200

14

10

6

2

2.4

2.0

1.6

1.2

MRI US

3D US/MRI Registration for Biopsy

Pathology/MRI Registration• Generate 3D histology

image• Non-rigid registration

of 3D MRI to 3D US

25

MAST vs TRUS bx (Bx Naïve)

Pokorny MR, Eur Urol 2014

Risk Stratification and Management

Cooperberg M et al., JCO 2010

40% 40% 20%

Walt Witmore:Where cure is possible, is it necessary?

Where necessary, is it possible?

Smart ManagementActive Surveillance for Low Risk

RP WWOM 56%

OM 69%

CSM 18%CSM 29%

12% T1c, mPSA 13

Overall Survival

HR 0.88 (95% CI, 0.71 to 1.08)p=0.22

Cause-Specific Survival

HR 0.63 (95% CI, 0.36 to 1.09)p = 0.09

CSS Forest Plot

75% low risk, mFU 6.4y (0.5 – 20.2y)

Chance of Discontinuing Surveillance

(n=267/993, 27%)

Klotz L et al., JCO 2014

CSS Active Surveillance N=993

15y CSS 94%10y CSS 98%

15 PC deaths28 M1p=0.18

Low- vs Int Riskn = 708 v 218

HR 3.74

89%

97%

Cause Specific Survival Metastases Free Survival

Multivariate AnalysisPredictive factors p-value HR (95% CI)PSA DT (≤3 years vs >3 years) 0.0062 3.7 (1.4, 9.4)

Gleason 7 vs ≤ 6 0.0181 3.0 (1.2, 7.3)

Baseline PSA >10 vs GS 7 inIntermediate risk groupBaseline Gleason 7 vs ≤ 6

HR 3.0

77%

94%

77%

93%

How Does AS compare to Active Treatment for Low Risk

Pr Ca?

bDFS stratified by Treatment Modality

Musurunu BH et al., JCO 33(Suppl 7); 2015 (abstr 178)

n=594 low risk prostate cancer, 2006-2008, no ADT

n 7y bDFS Dept $76 90.1% $6,98783 95.6% $1,470185 93.6% $3,384178 94.4% ?59 89.5% $7,029

System Savings with AS

Dragomar A, Cury FL, Aprikian AJ. CMAJ Open 2(2):e60-68; 2014

$100,000,000 per year!

Better Treatment

HR 0.23LDR-PB ARMN=188

EBRT ARMN=195

PSA

< 0.

282%

32%

Morris WJ et al., GU Symp 2015

RP for High Risk Disease

Crook J et al., Brachy 2014

BrachytherapySurgery45%

80%

MRI Reduces Overall Surgical Positive Margin Rate

0 1

p= 0.025

MRI

Posi

tiveM

argi

ns0.

000.

050.

100.

150.

20

Margolis et al. Radiology, 2012

N=1041.5 T ERC27% change in surgical approach

Conclusions• Screening for prostate cancer reduces risk

of metastases and dying of prostate cancer

• Diagnostic harms can be reduced by risk adaption, use of MR and TP biopsies

• Treatment harms can be reduced by using active surveillance for low risk patients

• High risk patients should be treated with most effective / cost-effective treatments up front